Control of whole-body glucose metabolism by central lactate in the presence of antipsychotics

The brain-liver axis is important in maintaining whole-body glucose homeostasis. Antipsychotics are used to treat schizophrenia, but one of their side-effects is disruption of metabolism. We previously reported that the antipsychotics olanzapine and haloperidol block the ability of central glucose to stimulate whole-body glucose metabolism and suppress glucose production by the liver (EGP, endogenous glucose production).

Both effects by central glucose require the conversion of glucose to lactate centrally. In the current study, we therefore examined whether antipsychotics affect the ability of central lactate to stimulate whole-body glucose metabolism and suppress EGP. Using our previous model of central (third ventricle to target the hypothalamus) infusion, acute subcutaneous administration of antipsychotics, and the pancreatic euglycemic clamp in rats, we found that olanzapine completely inhibited the ability of central lactate to stimulate whole-body glucose metabolism and partially blocked central lactate-induced suppression of EGP.

Since activation of the hypothalamus-liver axis of glycemic control requires central glucose and lactate to be metabolized, relevant pathways were also investigated. The adverse effects of olanzapine on central lactate sensing were not associated with decreased levels of citrate, a tricarboxylic acid cycle intermediate, in the hypothalamus or robust alterations in hypothalamic mitochondrial complex I activity assessed with the positron emission tomography tracer [18F]BCPP-EF. In summary, olanzapine impairs the ability of central lactate to control whole-body glucose metabolism and partially inhibits suppression of EGP by central lactate.

S.P. was awarded a Discovery Fund Postdoctoral Fellowship from the Centre for Addiction and Mental Health (CAMH). R.S. was awarded a Canadian Institutes of Health Research (CIHR) postdoctoral fellowship. B.H. was awarded scholarships from Banting & Best Diabetes Centre (BBDC), CIHR, and University of Toronto School of Graduate Studies.

F.d’O. was awarded a Fellowship from the Swiss National Foundation. Metabolites were analyzed at the University of Ottawa Metabolomics Core Facility, which is supported by the Terry Fox Foundation and Ottawa University. M.K.H. is funded by grants from CIHR, BBDC, and PSI foundation.

M.K.H. is the Kelly and Michael Meighen Chair in Psychosis Prevention. S.M.A. is supported in part by the Canada Research Chairs program and the CAMH Discovery Fund. N.V. acknowledges funding from the Azrieli Foundation, the Canada Research Chairs Program, Canada Foundation for Innovation, and the Ontario Research Fund.